Wing-Hang Tong, Nunziata Maio, De-Liang Zhang, Erika M. Palmieri, Hayden Ollivierre, Manik C. Ghosh, Daniel W. McVicar and Tracey A. Rouault; Blood Advances 2018 2:1146-1156; doi: doi:10.1182/bloodadvances.2018015669
hese results reveal new regulatory pathways and novel roles of the Fe-S cluster biogenesis machinery in modifying the epigenome and acetylome and provide new insights into the etiology of Fe-S cluster biogenesis disorders.
Interestingly, we showed that silencing of FXN and ISCU resulted in increased MEC17 levels and increased α-tubulin acetylation.
Extensive chromatin immunoprecipitation data collected at the FRDA locus, which contains an expanded trinucleotide repeat (GAA)n in the first intron of FXN, had shown that the levels of the heterochromatin mark H3K9me3 were enriched, whereas the levels of acetylated H3 and H4 were reduced. Our finding that decreased Fe-S cluster biogenesis resulted in decreased overall histone acetylation and increased H3K9me3 levels poses an interesting possibility of a negative feedback mechanism that potentiates a progressive loss of FXN expression in the postmitotic cells that are most severely affected in FRDA. Furthermore, our results showed that silencing of Fe-S cluster biogenesis factors reduced the levels of ELP3, a subunit of the Elongator complex that has roles in growth cone motility and axonal outgrowth. In addition, our studies revealed that silencing of FXN or ISCU induced the α-tubulin acetyltransferase MEC17, resulting in hyperacetylation of α-tubulin. Reversible acetylation of tubulin confers mechanical protection to microtubules51 and controls their interaction with cellular components52 and is critical for neuronal development and function, growth factor or apoptotic signaling, and cell cycle progression. Acetylation of K40 of α-tubulin is mainly controlled by the cytosolic acetyltransferase MEC17 and the cytosolic deacetylases HDAC6 and SIRT2. Notably, a mouse model of FRDA cardiomyopathy with ablation of FXN had increased mitochondrial protein acetylation that was attributed to a decrease in the mitochondrial NAD+/NADH ratio, which can lower the activity of the mitochondrial deacetylase SIRT3. Thus, our findings suggest that the roles of PDHc, ELP3, and MEC17 in the etiology of FRDA, GLRX5-related sideroblastic anemias, and other Fe-S cluster biogenesis disorders warrant further study.
Tuesday, May 29, 2018
Saturday, May 26, 2018
Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich’s ataxia patients
Daniel Nachun, Fuying Gao, Charles Isaacs, Cassandra Strawser, Zhongan Yang, Deepika Dokuru, Victoria Van Berlo, Renee Sears, Jennifer Farmer, Susan Perlman, David R Lynch, Giovanni Coppola; Human Molecular Genetics, ddy198, doi:10.1093/hmg/ddy198
We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression.
We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression.
A missed Fe-S cluster handoff causes a metabolic shakeup
Olivier Berteau; The Journal of Biological Chemistry 293, 8312-8313. doi: 10.1074/jbc.H118.002883
these findings hold significance for the biochemical and medical communities because the cellular phenotype induced mirrors pathological conditions encountered, for example, in nonadipose tissues such as heart and liver with possible connections to Friedreich's ataxia, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. Further research at the intersection between Fe-S cluster biogenesis and cellular metabolism is thus more than likely to bring unexpected insights into the pathogenesis of poorly understood diseases.
these findings hold significance for the biochemical and medical communities because the cellular phenotype induced mirrors pathological conditions encountered, for example, in nonadipose tissues such as heart and liver with possible connections to Friedreich's ataxia, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. Further research at the intersection between Fe-S cluster biogenesis and cellular metabolism is thus more than likely to bring unexpected insights into the pathogenesis of poorly understood diseases.
Acute loss of iron–sulfur clusters results in metabolic reprogramming and generation of lipid droplets in mammalian cells
Daniel R. Crooks, Nunziata Maio§, Andrew N. Lane, Michal Jarnik, Richard M. Higashi, Ronald G. Haller, Ye Yang, Teresa W-M. Fan, W. Marston Linehan and Tracey A. Rouault; The Journal of Biological Chemistry 293, 8297-8311. doi: 10.1074/jbc.RA118.001885
Elucidation of the mechanisms of citrate and lipid droplet accumulation in nonadipose tissues during disease states may reveal important insights into the pathogenesis of a significant number of poorly understood diseases.
Elucidation of the mechanisms of citrate and lipid droplet accumulation in nonadipose tissues during disease states may reveal important insights into the pathogenesis of a significant number of poorly understood diseases.
Friday, May 25, 2018
Improving the analysis of composite endpoints in rare disease trials
Martina McMenami, Anna Berglind and James M. S. Wason; Orphanet Journal of Rare Diseases 201813:81 doi:10.1186/s13023-018-0819-1
In rare diseases where there are few or no available treatments and limited opportunity to test emerging new treatments, the power to detect an effective treatment is of critical importance. The augmented binary method with small sample adjustments offers a substantial improvement for trials in these populations over methods currently being used, which throw away valuable information. We recommend the use of the augmented binary method in relevant rare disease trials using composite endpoints and supply R code to assist with the implementation.
In rare diseases where there are few or no available treatments and limited opportunity to test emerging new treatments, the power to detect an effective treatment is of critical importance. The augmented binary method with small sample adjustments offers a substantial improvement for trials in these populations over methods currently being used, which throw away valuable information. We recommend the use of the augmented binary method in relevant rare disease trials using composite endpoints and supply R code to assist with the implementation.
Biomimetic Artificial Epigenetic Code for Targeted Acetylation of Histones
Junichi Taniguchi, Yihong Feng, Ganesh N. Pandian, Fumitaka Hashiya, Takuya Hidaka, Kaori Hashiya, Soyoung Park, Toshikazu Bando, Shinji Ito, and Hiroshi Sugiyama; . Am. Chem. Soc., Article ASAP DOI: 10.1021/jacs.8b01518 Publication Date (Web): May 24, 2018
Recently, Ansari’s group reported a conjugate called Syn-TEF by coupling a PIP with another bromodomain inhibitor(+)-JQ1, selective to the bromodomain and extraterminal(BET) protein family. 45 Syn-TEF1 targeting expanded GAA repeats in the frataxin (FXN) gene successfully recruited BET protein BRD4 (bromodomain 4) to the gene locus in Friedreich’s ataxia (FRDA) patient-derived cells, resulting intranscriptional elongation of FXN. However, Syn-TEF and Bi-PIP target different members of the BD protein family and, therefore, are demonstrated to cause different outcomes; i.e.,while Syn-TEF causes BRD4-dependent transcriptional elongation, Bi-PIP causes P300 dependent histone acetylation. Thus,Bi-PIP and Syn-TEF can be used for different purposes, and this allows us to expand the range of potential applications of the synthetic epigenetic regulators.
Recently, Ansari’s group reported a conjugate called Syn-TEF by coupling a PIP with another bromodomain inhibitor(+)-JQ1, selective to the bromodomain and extraterminal(BET) protein family. 45 Syn-TEF1 targeting expanded GAA repeats in the frataxin (FXN) gene successfully recruited BET protein BRD4 (bromodomain 4) to the gene locus in Friedreich’s ataxia (FRDA) patient-derived cells, resulting intranscriptional elongation of FXN. However, Syn-TEF and Bi-PIP target different members of the BD protein family and, therefore, are demonstrated to cause different outcomes; i.e.,while Syn-TEF causes BRD4-dependent transcriptional elongation, Bi-PIP causes P300 dependent histone acetylation. Thus,Bi-PIP and Syn-TEF can be used for different purposes, and this allows us to expand the range of potential applications of the synthetic epigenetic regulators.
Sunday, May 20, 2018
Voyager Therapeutics Announces Additional Data at the American Society of Gene and Cell Therapy 2018 Annual Meeting
CAMBRIDGE, Mass., May 18, 2018 (GLOBE NEWSWIRE) -- Voyager Therapeutics, Inc. (NASDAQ:VYGR), a clinical-stage gene therapy company focused on developing life-changing treatments for severe neurological diseases today announced additional data presentations at the American Society of Gene and Cell Therapy (ASGCT) taking place May 16-19, 2018, in Chicago, Ill.
Oral Presentation Title: "Rescue of Central and Peripheral Neurological Phenotype in a Mouse Model of Friedreich's Ataxia by Intravenous Delivery of AAV Frataxin with a Novel Capsid" Abstract O672.
Data presented at this year's ASGCT meeting demonstrated in a transgenic mouse model of FA, that one-time, post-symptomatic IV dosing of Voyager's vector composed of a novel AAV capsid and a frataxin transgene durably improved motor function and rescued the FA phenotype based on multiple functional tests of sensory and motor behavior.
Oral Presentation Title: "Rescue of Central and Peripheral Neurological Phenotype in a Mouse Model of Friedreich's Ataxia by Intravenous Delivery of AAV Frataxin with a Novel Capsid" Abstract O672.
Data presented at this year's ASGCT meeting demonstrated in a transgenic mouse model of FA, that one-time, post-symptomatic IV dosing of Voyager's vector composed of a novel AAV capsid and a frataxin transgene durably improved motor function and rescued the FA phenotype based on multiple functional tests of sensory and motor behavior.
Thursday, May 17, 2018
Pediatric Ataxia: Focus on Chronic Disorders.
Lynch DR, McCormick A, Schadt K, Kichula E.; Semin Pediatr Neurol. 2018 Apr;25:54-64. doi: 10.1016/j.spen.2018.01.001.
FRDA is the most common ataxia, and its phenotype is readily recognized. In children of typical age, it is frequently possible to diagnose FRDA by examination and genetic testing without the need for adjunctive tests (MRI and EMG). Genetic confirmation is required for diagnosis. In addition, one must remember that all patients with FRDA identified have at least one expanded GAA repeat. Thus GAA repeat expansion testing should occur before sequencing for point mutations. (This is a common mistake in genetic testing). Currently, genetic panels and exome sequencing does not include the ability to test for repeats, so this testing must be requested separately.
FRDA is the most common ataxia, and its phenotype is readily recognized. In children of typical age, it is frequently possible to diagnose FRDA by examination and genetic testing without the need for adjunctive tests (MRI and EMG). Genetic confirmation is required for diagnosis. In addition, one must remember that all patients with FRDA identified have at least one expanded GAA repeat. Thus GAA repeat expansion testing should occur before sequencing for point mutations. (This is a common mistake in genetic testing). Currently, genetic panels and exome sequencing does not include the ability to test for repeats, so this testing must be requested separately.
DNA triplex structure, thermodynamics, and destabilisation: insight from molecular simulations
Belinda J. Boehm, Charles Whidborne, Alexander L. Button, Tara L. Pukala and David M. Huang; Phys Chem Chem Phys. 2018 May 10. doi: 10.1039/c8cp02385a
A structural analysis of the DNA triplexes that can form with the FRDA-related duplex sequence indicates that the triplex with a parallel homopyrimidine TFO is likely to be more stable than the antiparallel homopurine-TFO triplex, which may have implications for disease onset and treatment.
A structural analysis of the DNA triplexes that can form with the FRDA-related duplex sequence indicates that the triplex with a parallel homopyrimidine TFO is likely to be more stable than the antiparallel homopurine-TFO triplex, which may have implications for disease onset and treatment.
Cardiovascular and sudomotor autonomic assessment in Friedreich’s Ataxia
Karen A. Girotto Takazaki, Alberto Martinez, Thiago Junqueira Rezende, Carelis González-Salazar, Anamarli Nucci, Iscia Lopes-Cendes, Marcondes C. Franca; Clinical Neurophysiology, Volume 129, Supplement 1, May 2018, Pages e86
doi:10.1016/j.clinph.2018.04.216
Sudomotor, but not cardiovascular autonomic dysfunction is frequent in FDRA. Small cholinergic post-ganglionic nerve fibers are affected in the disease.
doi:10.1016/j.clinph.2018.04.216
Sudomotor, but not cardiovascular autonomic dysfunction is frequent in FDRA. Small cholinergic post-ganglionic nerve fibers are affected in the disease.
Subscribe to:
Posts (Atom)
